Co‐Treatment With rhBMP‐2 and Rapamycin Modulates Osteogenesis–Adipogenesis Balance to Enhance Aged Bone Regeneration

ABSTRACT Recombinant human bone morphogenetic protein 2 (rhBMP‐2) is a well‐established osteoinductive agent used in clinical practice. In this study, rhBMP‐2 is found to exacerbate the imbalance between osteogenesis and adipogenesis in senescent bone marrow stromal cells (BMSCs), resulting in excess adipocytes (eADs) accumulation and a diminished osteogenic response. However, the role of eADs in age‐related bone repair deficits remains unclear. Our findings indicate that eADs within the aged microenvironment contribute to impaired bone regeneration by promoting BMSC senescence and suppressing osteogenic differentiation. To address this issue, we investigated the feasibility of regulating the abnormal differentiation of senescent BMSCs to enhance aged bone regeneration. Based on this, a novel energy‐supplying hydrogel system (PEGSN‐PGA/rhBMP‐2/Rapa, PBR) suitable for the aged regenerative microenvironment and with excellent bone integration performance is designed for local minimally invasive treatment of aged bone defects. This system effectively regulates the abnormal differentiation of senescent BMSCs, maintains the cell cycle process, and retains the regenerative potential for bone repair in the senescent microenvironment. This study presents a novel strategy for the treatment of rhBMP‐2‐mediated bone degenerative diseases and offers a pioneering perspective on the interplay among adipogenesis, cellular senescence, and bone regeneration during the aging process